Tiotropium inhalation solution for nebulization

ABSTRACT

The present invention relates to a sterile pharmaceutical composition comprising tiotropium or a pharmaceutically acceptable salt thereof, for inhalation via nebulization to a subject (e.g. a human). The invention also relates to a process for preparing the pharmaceutical composition and its use in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) in a subject.

RELATED APPLICATIONS

This patent application is a continuation-in-part of U.S. patentapplication Ser. No. 15/157,143, filed May 17, 2016, which claimspriority to Indian Provisional Patent Application number 1945/MUM/2015filed on May 18, 2015, each of which is hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to a sterile pharmaceutical compositioncomprising tiotropium or a pharmaceutically acceptable salt thereof, forinhalation via nebulization to a subject (e.g. a human) The inventionalso relates to a process for preparing the pharmaceutical compositionand its use in the treatment of respiratory diseases such as chronicobstructive pulmonary disease (COPD) in a subject.

BACKGROUND OF THE INVENTION

Anticholinergic agents are believed to inhibit vagally-mediated reflexesby blocking acetylcholine at the cholinergic receptor. Anticholinergicagents are also believed to inhibit secretions of the serous andsero-mucous glands of the nasal mucosa. Anticholinergic agents for thetreatment or control of respiratory disorders include tiotropium,oxitropium, ipratropium, glycopyrrolate, aclidinium, and salts thereof.

One known anticholinergic agent is tiotropium bromide, the chemical nameof which is (1α, 2ß, 4ß, 5α, 7ß)-7-[(hydroxydi-2-thienylacetyl) oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.02, 4] nonane bromidemonohydrate. Tiotropium bromide is commercially marketed in the UnitedStates by Boehringer Ingelheim Pharmaceuticals, Inc. as SPIRIVA®capsules containing lactose and 18 μg tiotropium (equivalent to 22.5 μgtiotropium bromide monohydrate) and inhalation solution SPIRIVA®RESPIMAT containing tiotropium bromide, water for injection, edetatedisodium, benzalkonium chloride and hydrochloric acid. Tiotropiumbromide is indicated for the maintenance treatment of bronchospasmassociated with COPD and for reducing COPD exacerbations.

US 2004/0019073 discloses an aqueous inhalation solution comprisingtiotropium and the preservative benzalkonium chloride.

Inhalation solutions generally contain preservatives such asbenzalkonium chloride. Frequent exposure to low concentrations ofbenzalkonium chloride may lead to adverse effects. Some studies (Beasleyet al., 1987, British Medical Journal, Vol 294, 1197-1198; Beasley etal., 1988, Br. J. Clin. Pharmac. 25, 283-287; Miszkiel et al., 1988, Br.J. Clin. Pharmac. 25, 157-163) also suggest that repeated use of COPDtreatments with benzalkonium chloride may result in paradoxicbronchoconstriction, as benzalkonium chloride has bronchoconstrictorproperties 7.4 times less potent than histamine. Moreover, exposure tobenzalkonium chloride may lead to occupational asthma and may also causedose-dependent bronchoconstriction.

Treatments for COPD often come in multiple dosage units and must bediluted to specific concentrations suitable for treating patients, or bedirectly delivered with the help of a costly and complicated device.This poses several problems while preparing the final dose and/or devicefor delivery. For example, COPD treatments requiring administration of asingle dose unit from multiple dosage units sometimes lack proper mixingor diluting instructions, or the instructions for preparing and usingthe COPD treatment may be hard to follow or can be easily lost. Of evengreater concern is haphazard diluting or mixing of COPD medications,which can result in administering the wrong dosage. This could beespecially harmful for patients those are less tolerant to higherdosages of asthma medications. Incorrect mixing can also result intreatment failure such that additional medical attention is required,thereby increasing the time, expense and personnel costs associated withtherapy.

There is, therefore, a need for an improved inhalation solution, system,kit and method for relieving symptoms associated with COPD.

SUMMARY OF THE INVENTION

The present invention relates to a sterile pharmaceutical compositionfor inhalation via nebulization to a patient (e.g., a human) Thepharmaceutical composition comprises tiotropium or its salt (e.g., apharmaceutically acceptable salt) and water. The pharmaceuticalcomposition may be a solution. The pharmaceutical composition may becontained within a container suitable for nebulization. Thepharmaceutical composition may be administered in nebulized form torelieve bronchospasm in patients suffering from COPD or for reducingCOPD exacerbations.

In one embodiment a sterile pharmaceutical composition is a unit dosenebulizable pharmaceutical solution for inhalation comprising tiotropiumor its salt. The pharmaceutical solution may be administered innebulized form to relieve bronchospasm in a subject, such as a subjectsuffering from COPD.

In a preferred embodiment, the pharmaceutical composition or solution isfree, or substantially free, of preservative including, but not limitedto, quaternary ammonium preservatives, such as a benzalkonium salt,(e.g., benzalkonium chloride). For example, the pharmaceuticalcomposition or solution may contain less than about 0.1% by weight ofpreservative (or quaternary ammonium preservative) (such as less thanabout 0.05%, less than about 0.02%, or less than about 0.008%), based on100% total weight of composition or solution.

Yet another embodiment is a sterile, unit dose nebulizablepharmaceutical solution for inhalation comprising tiotropium or its saltwherein the composition is free, or substantially free, of complexingagent (such as ethylene diamine tetra-acetic acid (EDTA). For example,the pharmaceutical composition or solution may contain less than about0.1% by weight of complexing agent (such as less than about 0.05%, lessthan about 0.02%, or less than about 0.008%), based on total weight ofcomposition or solution.

One embodiment is a pharmaceutical composition comprising

-   -   (i) tiotropium or its pharmaceutically acceptable salts thereof    -   (ii) water        wherein said composition is free of preservative and complexing        agent.

Yet another embodiment is a sterile nebulizable pharmaceutical solutionfor inhalation via nebulization comprising tiotropium or its salt,wherein the composition is free, or substantially free, of (a) EDTA or asalt thereof and (b) a benzalkonium salt, such as benzalkonium chloride.

In a preferred embodiment, the tiotropium salt in the pharmaceuticalcomposition or pharmaceutical solution described herein is tiotropiumbromide, such as tiotropium bromide monohydrate((1α,2β,4β,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonanebromide, monohydrate).

In another embodiment, the tiotropium salt in the pharmaceuticalcomposition or pharmaceutical solution described herein is amorphoustiotropium bromide.

In another embodiment, the tiotropium salt in the pharmaceuticalcomposition or pharmaceutical solution described herein is anhydroustiotropium bromide.

In another embodiment, the tiotropium salt in the pharmaceuticalcomposition or pharmaceutical solution described herein is anhydrousamorphous tiotropium bromide.

The pharmaceutical composition or solution may include from about 0.001mg to about 0.3 mg of tiotropium or its salt (such as tiotropiumbromide), such as from about 0.010 mg to about 0.280 mg; about 0.020 mgto about 0.260 mg; about 0.025 mg to about 0.240 mg; about 0.005 mg toabout 0.1 mg; about 0.005 mg to about 0.05 mg; about 0.01 mg to about0.04 mg; about 0.02 to about 0.07 mg; about 0.04 mg to about 0.08 mg;about 0.04 mg to about 0.10 mg; about 0.05 mg to about 0.15 mg; about0.10 mg to about 0.19 mg; about 0.15 mg to about 0.20 mg; about 0.20 mgto about 0.25 mg; or from about 0.26 mg to about 0.30 mg tiotropium orits salt. The pharmaceutical composition or solution may include fromabout 0.001 mg to about 0.3 mg of tiotropium or its salt (such astiotropium bromide), such as from about 0.010 mg to about 0.280 mg;about 0.020 mg to about 0.260 mg; about 0.025 mg to about 0.240 mg;about 0.005 mg to about 0.1 mg; about 0.005 mg to about 0.05 mg; about0.01 mg to about 0.04 mg; about 0.02 to about 0.07 mg; about 0.04 mg toabout 0.08 mg; about 0.04 mg to about 0.10 mg; about 0.05 mg to about0.15 mg; about 0.10 mg to about 0.19 mg; about 0.15 mg to about 0.20 mg;about 0.20 mg to about 0.25 mg; or from about 0.26 mg to about 0.30 mgtiotropium per unit dosage of pharmaceutical composition or solution.

The pharmaceutical composition or solution may include from about 1 μgto about 100 μg of tiotropium or its salt (such as tiotropium bromide),such as from about 10 μg to about 80 μg, for example, about 5 μg, about10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg,about 40 μg, about 45 μg, about 50 μg, about 55 μg, about 60 μg, about65 μg, about 70 μg, about 75 μg, about 80 μg, about 85 μg, about 90 μg,about 95 μg, or about 100 μg of tiotropium or its salt. In one preferredembodiment, the volume of the pharmaceutical composition or solution is2 mL.

One embodiment is a 2 mL pharmaceutical composition, such as a solution,containing about 80 μg tiotropium bromide. Another embodiment is a 2 mLpharmaceutical composition, such as a solution, containing about 75 μgtiotropium bromide. Yet another embodiment is a 2 mL pharmaceuticalcomposition, such as a solution, containing about 70 μg tiotropiumbromide. Yet another embodiment is a 2 mL pharmaceutical composition,such as a solution, containing about 65 μg tiotropium bromide. Yetanother embodiment is a 2 mL pharmaceutical composition, such as asolution, containing about 60 μg tiotropium bromide. Yet anotherembodiment is a 2 mL pharmaceutical composition, such as a solution,containing about 55 μg tiotropium bromide. Yet another embodiment is a 2mL pharmaceutical composition, such as a solution, containing about 50μg tiotropium bromide. Yet another embodiment is a 2 mL pharmaceuticalcomposition, such as a solution, containing about 45 μg tiotropiumbromide. Yet another embodiment is a 2 mL pharmaceutical composition,such as a solution, containing about 40 μg tiotropium bromide. Yetanother embodiment is a 2 mL pharmaceutical composition, such as asolution, containing about 35 μg tiotropium bromide. Yet anotherembodiment is a 2 mL pharmaceutical composition, such as a solution,containing about 30 μg tiotropium bromide. Yet another embodiment is a 2mL pharmaceutical composition, such as a solution, containing about 25μg tiotropium bromide. Yet another embodiment is a 2 mL pharmaceuticalcomposition, such as a solution, containing about 20 μg tiotropiumbromide. Yet another embodiment is a 2 mL pharmaceutical composition,such as a solution, containing about 15 μg tiotropium bromide. Yetanother embodiment is a 2 mL pharmaceutical composition, such as asolution, containing about 10 μg tiotropium bromide. Yet anotherembodiment is a 2 mL pharmaceutical composition, such as a solution,containing about 5 μg tiotropium bromide.

The pharmaceutical composition or solution may include from about0.0001% to about 0.030% by weight tiotropium or its salt (such astiotropium bromide), such as from about 0.0002 wt % to about 0.02 wt %;about 0.0003 wt % to about 0.01 wt %; about 0.0005 wt % to about 0.008wt %; about 0.0002 wt % to about 0.001 wt %; about 0.001 wt % to about0.005 wt %; about 0.006 wt % to about 0.010 wt %; about 0.011 wt % toabout 0.015 wt %; about 0.016 wt % to about 0.020 wt %; about 0.021 wt %to about 0.025 wt %; or from about 0.026 wt % to about 0.030 wt %tiotropium or its salt, based on 100% total weight of pharmaceuticalcomposition or solution.

In additional embodiments, the complexing agent (such as disodium EDTA)is present in the pharmaceutical composition or solution at aconcentration of less than about 0.1% by weight, such as less than about0.09%, less than about 0.08%, less than about 0.07%, less than about0.06%, less than about 0.05%, less than about 0.04%, less than about0.03%, about 0.02%, or less than about 0.01% by weight.

In additional embodiments, the pharmaceutical composition or solutionmay contain about 0.01% complexing agent about 0.02% complexing agent,about 0.03% complexing agent, about 0.04% complexing agent, about 0.05%complexing agent, about 0.06% complexing agent, about 0.07% complexingagent, about 0.08% complexing agent about 0.09% complexing agent orabout 0.1% complexing agent by weight.

In additional embodiments, the pharmaceutical composition or solutionmay contains about 0.01% disodium EDTA, about 0.02% disodium EDTA, about0.03% disodium EDTA, about 0.04% disodium EDTA, about 0.05% disodiumEDTA, about 0.06% disodium EDTA, about 0.07% disodium EDTA about 0.08%disodium EDTA about 0.09% disodium EDTA or about 0.1% disodium EDTA byweight. In one preferred embodiment, the pharmaceutical composition orsolution contains about 0.01% disodium EDTA. In another preferredembodiment, the pharmaceutical composition or solution contains about0.02% disodium EDTA. In yet another preferred embodiment, thepharmaceutical composition or solution contains about 0.05% disodiumEDTA.

One embodiment is a pharmaceutical solution suitable for administrationwith a nebulizer consisting essentially of

-   -   (a) about 0.0005% to about 0.008% w/w tiotropium or a        pharmaceutically acceptable salt thereof,    -   (b) about 0% to about 0.008% disodium EDTA;    -   (c) about 0% to about 0.9% sodium chloride; and    -   (d) water,        based upon 100% total weight of the pharmaceutical solution,        wherein the pH of the pharmaceutical composition is about 2 to        about 4 (such as about 2.7). In one preferred embodiment, the        pharmaceutical solution is free, or substantially free, of        quaternary ammonium preservatives. In another preferred        embodiment, the pharmaceutical solution is free, or        substantially free, of preservatives.

In one embodiment, the pharmaceutical composition or solution providedherein has a long shelf life, i.e., it is stable during long termstorage. The pharmaceutical composition or solution may contain greaterthan about 80%, such as greater than about 85%, greater than about 90%,greater than about 95% or greater than about 98% of the initial amountof tiotropium or its salt in the pharmaceutical composition or solutionafter being stored for 3 or 6 months or 1, 2 or 3 years at 25° C. whenstored in a suitable low density polyethylene (LDPE) container.

Yet another embodiment is a container containing a pharmaceuticalcomposition or solution of the present invention, wherein the volume ofthe composition or solution is from about 0.1 ml to about 5 ml, such asfrom about 1 ml to about 3 ml, or from about 1.5 ml to about 2.5 ml. Inanother embodiment, the volume of the tiotropium solution of the presentinvention is from about 0.05 ml to about 1.0 ml; such as from about 0.1ml to about 0.9 ml; from about 0.1 ml to about 0.8 ml; from about 0.1 mlto about 0.7 ml; from about 0.1 ml to about 0.6 ml; from about 0.1 ml toabout 0.5 ml; from about 0.1 ml to about 0.4 ml; from about 0.1 ml toabout 0.3 ml; or from about 0.1 ml to about 0.2 ml.

The pharmaceutical composition or solution may have a pH of betweenabout 2.0 and about 6.0. For example, the pharmaceutical composition orsolution may have a pH of from about 2.0 to about 4.0. The preferred pHrange of tiotropium bromide solutions is from about 2.0 to about 4.5,preferably from about 2.5 to 3.5, most preferably from about 2.7 toabout 3.2. In one embodiment, the pharmaceutical composition or solutionhas a pH of about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about3.0, about 3.1, about 3.2, about 3.3, about 3.4, or about 3.5.

In another embodiment of the present invention, the inhalation solutionhas a pH from about 2.2 to about 2.9.

The osmolality of the pharmaceutical composition or solution may be fromabout 200 to about 500 mOsm/kg. In other embodiments of the presentinvention, the osmolality of the solution may be between about 275 andabout 325 mOsm/kg.

In another embodiment, the pharmaceutical composition of the presentinvention comprises about 0.002% to about 0.01% w/w tiotropium or anypharmaceutically acceptable salt thereof, about 0% to about 0.01% w/wEDTA, about 0.9% sodium chloride, wherein the composition is free ofpreservative and wherein the composition has a pH in the range of about2.0 to about 4.0.

Another embodiment is a prepackaged, sterile, premixed, premeasuredtiotropium bromide inhalation solution. Preferably, the solution is aready-to-use solution which does not require any mixing or dilution bythe subject prior to administration. The solution may be administeredfor the relief of bronchospasm in a subject suffering from COPD.

Yet another embodiment is one or more prefilled containers containing apharmaceutical composition or solution of the present invention. In oneembodiment, each container comprises a single unit dose of apharmaceutical composition or solution of the present inventioncomprising a therapeutically effective amount of tiotropium or its saltfor the treatment of COPD. In one embodiment, each container includes asterile, premixed, premeasured, substantially benzalkonium chloride freeinhalation solution comprising a single unit dose of a therapeuticallyeffective amount of tiotropium or its salt in a single container.

One embodiment is a prefilled container containing about 2 mL of anaqueous pharmaceutical composition consisting of (i) from about 10 toabout 80 μg of tiotropium bromide, (ii) sodium chloride, (iii)hydrochloric acid (e.g., in an amount sufficient to adjust the pH of thepharmaceutical composition, such as to about 2.5 to about 3.5), and (iv)about 0.01% by weight of disodium EDTA, wherein the composition is freeof preservative, and the composition has a pH of from about 2.5 to about3.5. The sodium chloride may be present at about 0.9% by weight. In oneembodiment, the pH of the pharmaceutical composition is about 2.7. Inanother embodiment, the pH of the pharmaceutical composition is about2.8. In yet another embodiment, the pH of the pharmaceutical compositionis about 2.9. In yet another embodiment, the pH of the pharmaceuticalcomposition is about 3.0.

Another embodiment is a prefilled container containing about 2 mL of anaqueous pharmaceutical composition consisting of (i) from about 10 toabout 80 μg of tiotropium bromide, (ii) sodium chloride, (iii)hydrochloric acid (e.g., in an amount sufficient to adjust the pH of thepharmaceutical composition, such as to about 2.5 to about 3.5), and (iv)about 0.02% by weight of disodium EDTA, wherein the composition is freeof preservative, and the composition has a pH of from about 2.5 to about3.5.

Yet another embodiment is a prefilled container containing about 2 mL ofan aqueous pharmaceutical composition consisting of (i) from about 10 toabout 80 μg of tiotropium bromide, (ii) sodium chloride, (iii)hydrochloric acid (e.g., in an amount sufficient to adjust the pH of thepharmaceutical composition, such as to about 2.5 to about 3.5), and (iv)about 0.05% by weight of disodium EDTA, wherein the composition is freeof preservative, and the composition has a pH of from about 2.5 to about3.5.

Yet another embodiment is a method of administering tiotropium or a saltthereof comprising administering by inhalation to a subject apharmaceutical composition or solution of the present invention.

Yet another embodiment is a method of relieving bronchospasm (such asthat associated with COPD) comprising administering by inhalation to asubject in need thereof a pharmaceutical composition or solution of thepresent invention.

Yet another embodiment is a kit and/or system for administering abronchodilator to relieve bronchospasm, for instance, bronchospasmassociated with COPD. The kit and/or system may comprise apharmaceutical composition or solution of the present invention. In oneembodiment, the kit and/or system comprises an inhalation solution ofthe present invention comprising a therapeutically effective amount oftiotropium in a prepackaged, premeasured, premixed and/or single unitdose form for the treatment of COPD. In another embodiment, theprepackaged inhalation kit and/or system comprises one or more premixed,premeasured single unit dose vials comprising a pharmaceuticalcomposition or solution of the present invention containing atherapeutically effective amount of tiotropium for the treatment ofbronchospasm (such as that associated with COPD), and instructions forusing the same.

Yet another embodiment is a kit comprising a nebulizer, instructions forusing the nebulizer and the unit dose vials containing thepharmaceutical compositions of the present invention.

Yet another embodiment is a kit for the treatment, prevention oramelioration or one or more symptoms of diseases or disorders associatedwith bronchoconstriction which comprises:

(i) a nebulizer;

(ii) a nebulizable composition for the treatment, prevention oramelioration or one or more symptoms of diseases or disorders associatedwith bronchoconstriction (such a pharmaceutical composition or solutionof the present invention) which comprises:

(a) tiotropium or its salt; and

(b) water.

A further embodiment of the present invention is to provide a processfor making an inhalation solution comprising tiotropium for use inrelieving bronchospasm associated with COPD. In one embodiment, theprocess comprises the steps of:

(a) dissolving tiotropium or its salt in water;

(b) optionally addition of pharmaceutically acceptable excipients suchas a buffer, complexing agent, tonicity adjusting agent, or anycombination thereof, to the solution of step (a);

(c) optionally adjusting the pH of the solution (for example, thesolution of step (a) or step (b)) with a pharmaceutically acceptableacid;

(d) optionally filtering the solution (for example, with a 0.2 micronfilter); and

(e) filling a suitable container with the solution.

In another embodiment, the process comprises the steps of:

(a) dissolving tiotropium or its salt in water;

(b) optionally addition of pharmaceutically acceptable excipients suchas a buffer, complexing agent, tonicity adjusting agent, or anycombination thereof, to the solution of step (a);

(c) optionally adjusting the pH of the solution (for example, thesolution of step (a) or step (b)) with a pharmaceutically acceptableacid;

(d) filtering the solution (for example, with a 0.2 micron filter); and

(e) filling a suitable container with the solution.

Yet another embodiment is a method of preparing a pharmaceuticalcomposition comprising about 0.0001% to about 0.03% by weight oftiotropium or a pharmaceutically acceptable salt thereof, water, about0.01% to about 0.1% by weight of a complexing agent, and about 0% toabout 0.9% by weight of sodium chloride, wherein the composition has apH ranging from about 2.5 to about 3.5 and is free of preservative. Theprocess includes the steps of:

(a) dissolving sodium chloride in water to form a solution;

(b) adding a complexing agent to the solution of step (a);

(c) adjusting the pH of the solution of step (b) (for example, by addinghydrochloric acid) to about 2.5 to about 3.5;

(d) adding tiotropium or a pharmaceutically acceptable salt thereof;

(e) filtering the solution of step (d); and

(f) filling a container with the solution of step (e).

Another embodiment of the invention relates to a device comprisingtiotropium or a salt thereof, for example, for use in relieving thesymptoms of COPD.

Yet another embodiment is a method for improving user compliance and/orquality of life as compared to conventional treatments for COPD. Themethod comprises initiating treatment with the pharmaceuticalcomposition or solution of the present invention, or a container, kit,or system of the present invention. The present invention providesconvenient, fast and reliable treatment for COPD that represents animprovement over traditional COPD treatments.

Other objects, features and advantages of the present invention will beapparent to those of ordinary skill in the art in view of the followingdetailed description of the invention and accompanying drawings.

DETAILED DESCRIPTION OF THE INVENTION

Salts of tiotropium include, but are not limited to, acid addition saltsand base salts thereof, solvates thereof, and any mixture thereof.Suitable salts of tiotropium include, but are not limited to, halidesalts such as bromide, chloride and iodide salts. These and other saltsare described, for example, in U.S. Patent No. RE 39,820, which ishereby incorporated by reference in its entirety. The preparation of thetiotropium bromide monohydrate is described in U.S. Pat. No. 6,777,423,which is incorporated herein by reference in its entirety. Tiotropiumand its salts can be administered to provide a bronchodilation effectand relief from symptoms associated with COPD.

Tiotropium bromide has a molecular weight of 472.416 g/mol and theempirical formula C₁₉H₂₂BrNO₄S₂. Tiotropium bromide monohydrate issparingly soluble in water and soluble in methanol. The establishedchemical structure of tiotropium bromide monohydrate is as follows:

The term “tiotropium” as used herein, include acids, salts, esters,hydrates, polymorphs, hemihydrates, solvates, and derivatives thereof.

2-hydroxy-2,2-dithiophen-2-ylacetic acid is an impurity of Tiotropiumidentified as Impurity A in the present invention.

In the present invention, tiotropium may be provided in a variety ofpharmaceutically acceptable vehicles, including, but not limited to,water or hydroalcoholic solution or any other aqueous solutioncomprising a pharmaceutically acceptable amount of an osmotic agent.

In a preferred embodiment, the tiotropium salt in the pharmaceuticalcomposition or pharmaceutical solution described herein is tiotropiumbromide, such as tiotropium bromide monohydrate((1α,2β,4β,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonanebromide, monohydrate).

In another embodiment, the tiotropium salt in the pharmaceuticalcomposition or pharmaceutical solution described herein is amorphoustiotropium bromide.

In another embodiment, the tiotropium salt in the pharmaceuticalcomposition or pharmaceutical solution described herein is anhydroustiotropium bromide.

In another embodiment, the tiotropium salt in the pharmaceuticalcomposition or pharmaceutical solution described herein is anhydrousamorphous tiotropium bromide.

To treat indications with a therapeutic agent, an “effective amount” ofa therapeutic agent will be recognized by clinicians and persons ofordinary skill in the art, and includes an amount effective to treat,reduce, alleviate, ameliorate, eliminate or prevent one or more symptomsof the condition sought to be treated, or alternately, the conditionsought to be avoided, or to otherwise produce a clinically recognizablefavorable change in the condition or its effects.

In another embodiment, the present invention provides sterilepharmaceutical composition of tiotropium for inhalation wherein thecomposition is substantially free of preservative, preferablysubstantially benzalkonium chloride free to treat bronchospasmassociated with COPD.

A composition is “substantially benzalkonium chloride free” or“substantially free of benzalkonium chloride” when the amount ofbenzalkonium chloride is not an amount sufficient to materially act as apreservative for the pharmaceutical composition or solution. Moreover,in a “substantially benzalkonium chloride free” or “substantially freeof benzalkonium chloride” composition, benzalkonium chloride may bepresent in concentration less than 0.008% w/w based on total weight ofcomposition or solution. The term “substantially free of preservative”denotes that preservative may be present in concentration less than0.008% w/w based on total weight of composition or solution.

Generally, pharmaceutical inhalation solutions contain a preservativesuch as benzalkonium chloride. One problem with these solutions is thatthe benzalkonium chloride may cause paradoxic bronchoconstriction if thesolution is administered repeatedly over short intervals and frequentexposure to benzalkonium chloride may lead to occupational asthma.Another problem is that, when inhaled by patients, the benzalkoniumchloride can cause dose-dependent bronchoconstriction. The inhalationsolutions of the present invention may be provided without benzalkoniumchloride, thereby making them suitable, especially in situations wherethe inhalation solution is administered repeatedly over a short periodof time. Also, administering a substantially benzalkonium chloride-freeinhalation solution to a patient reduces the concomitant liability ofadverse effects associated with benzalkonium chloride alone or incombination other excipients and/or tiotropium. It also negates thetoxicity and other side effects associated with benzalkonium chloride.

The inhalation solutions of the present invention may also be providedin sterile, unit dose treatments.

In another embodiment of the present invention, there is provided asterile, unit dose pharmaceutical solution composition for inhalationvia nebulization comprising tiotropium or its salt wherein thecomposition is substantially free of a complexing agent such as ethylenediamine tetra-acetic acid (EDTA).

One embodiment is a pharmaceutical composition comprising

-   -   (i) tiotropium or its pharmaceutically acceptable salts thereof    -   (ii) water        wherein said composition is free of preservative and complexing        agent.

Low pH levels, particularly below 3.2, are preferred for the long-termstability of the tiotropium salts in the formulation. The absence of orreduction in the concentration of the additive EDTA also helps to reducethe paradoxic effect associated with cough.

In another embodiment of the present invention, the inhalation solutionhas a pH of from about 2.0 to about 6.0. In another embodiment, thesolution has a pH of from about 2.0 to about 4.0. The preferred pH rangeof tiotropium bromide solutions is from about 2.0 to about 4.5,preferably from about 2.5 to 3.5, most preferably from about 2.7 toabout 3.2. In one embodiment, the pharmaceutical composition or solutionhas a pH of about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about3.0, about 3.1, about 3.2, about 3.3, about 3.4, or about 3.5.

In another embodiment of the present invention, the inhalation solutionhas a pH from about 2.2 to about 2.9.

The pH may be adjusted by the addition of one or more pharmaceuticallyacceptable acids. Examples of suitable pharmaceutically acceptable acidsinclude inorganic acids, such as hydrochloric acid, hydrobromic acid,nitric acid, sulfuric acid, and phosphoric acid, and combinationsthereof. Examples of other suitable pharmacologically acceptable acidsinclude organic acids, such as ascorbic acid, citric acid, malic acid,maleic acid, tartaric acid, succinic acid, fumaric acid, acetic acid,formic acid, and/or propionic acid. In one embodiment, the pH isadjusted with 1N hydrochloric acid or 1N sulfuric acid. In anotherembodiment, the pH is adjusted with one or more organic acids selectedfrom ascorbic acid, fumaric acid and citric acid. A preferred organicacid is citric acid. If desired, mixtures of the abovementioned acidsmay also be used, particularly in the case of acids which have otherproperties in addition to their acidifying properties, e.g., those whichact as flavorings or antioxidants, such as for example citric acid orascorbic acid.

The inhalation solution of the present invention may contain sodiumcitrate at a concentration of about 0.1 to about 1.0% (w/w) and citricacid at a concentration of about 0.1 to 1.0% (w/w) to control pH.

The inhalation solution may optionally include a buffer. General andbiological buffers in the pH range of about 2.0 to about 8.0 include,but are not limited to, acetate, barbital, borate, Britton-Robinson,cacodylate, citrate, collidine, formate, maleate, McIlvaine, phosphate,Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen),veronal acetate, MES, BIS-TRIS, ADA, ACES, PIPES, MOPSO, BIS-TRISPROPANE, BES, MOPS, TES, HEPES, DIPSO, MOBS, TAPSO, TRIZMA, HEPPSO,POPSO, TEA, EPPS, TRICINE, GLY-GLY, BICINE, HEPBS, TAPS, and AMPDbuffers.

In another embodiment of the present invention, a therapeuticallyeffective amount of tiotropium may include from about 0.001 mg to about0.3 mg of tiotropium bromide. Therapeutically effective amounts may alsoinclude the following intermediate ranges of tiotropium bromide: fromabout 0.010 mg to about 0.280 mg; about 0.020 mg to about 0.260 mg;about 0.025 mg to about 0.240 mg; about 0.005 mg to about 0.1 mg; about0.005 mg to about 0.05 mg; about 0.01 mg to about 0.04 mg; about 0.02 toabout 0.07 mg; about 0.04 mg to about 0.08 mg; about 0.04 mg to about0.10 mg; about 0.05 mg to about 0.15 mg; about 0.10 mg to about 0.19 mg;about 0.15 mg to about 0.20 mg; 0.20 mg to about 0.25 mg; and about 0.26mg to about 0.30 mg. The pharmaceutical composition or solution mayinclude from about 0.001 mg to about 0.3 mg of tiotropium or its salt(such as tiotropium bromide), such as from about 0.010 mg to about 0.280mg; about 0.020 mg to about 0.260 mg; about 0.025 mg to about 0.240 mg;about 0.005 mg to about 0.1 mg; about 0.005 mg to about 0.05 mg; about0.01 mg to about 0.04 mg; about 0.02 to about 0.07 mg; about 0.04 mg toabout 0.08 mg; about 0.04 mg to about 0.10 mg; about 0.05 mg to about0.15 mg; about 0.10 mg to about 0.19 mg; about 0.15 mg to about 0.20 mg;about 0.20 mg to about 0.25 mg; or from about 0.26 mg to about 0.30 mgtiotropium per unit dosage of pharmaceutical composition or solution.

The pharmaceutical composition or solution may include from about 1 μgto about 100 μg of tiotropium or its salt (such as tiotropium bromide),such as from about 10 μg to about 80 μg, for example, about 5 μg, about10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg,about 40 μg, about 45 μg, about 50 μg, about 55 μg, about 60 μg, about65 μg, about 70 μg, about 75 μg, about 80 μg, about 85 μg, about 90 μg,about 95 μg, or about 100 μg of tiotropium or its salt. In one preferredembodiment, the volume of the pharmaceutical composition or solution is2 mL.

One embodiment is a 2 mL pharmaceutical composition, such as a solution,containing about 80 μg tiotropium bromide. Another embodiment is a 2 mLpharmaceutical composition, such as a solution, containing about 75 μgtiotropium bromide. Yet another embodiment is a 2 mL pharmaceuticalcomposition, such as a solution, containing about 70 μg tiotropiumbromide. Yet another embodiment is a 2 mL pharmaceutical composition,such as a solution, containing about 65 μg tiotropium bromide. Yetanother embodiment is a 2 mL pharmaceutical composition, such as asolution, containing about 60 μg tiotropium bromide. Yet anotherembodiment is a 2 mL pharmaceutical composition, such as a solution,containing about 55 μg tiotropium bromide. Yet another embodiment is a 2mL pharmaceutical composition, such as a solution, containing about 50μg tiotropium bromide. Yet another embodiment is a 2 mL pharmaceuticalcomposition, such as a solution, containing about 45 μg tiotropiumbromide. Yet another embodiment is a 2 mL pharmaceutical composition,such as a solution, containing about 40 μg tiotropium bromide. Yetanother embodiment is a 2 mL pharmaceutical composition, such as asolution, containing about 35 μg tiotropium bromide. Yet anotherembodiment is a 2 mL pharmaceutical composition, such as a solution,containing about 30 μg tiotropium bromide. Yet another embodiment is a 2mL pharmaceutical composition, such as a solution, containing about 25μg tiotropium bromide. Yet another embodiment is a 2 mL pharmaceuticalcomposition, such as a solution, containing about 20 μg tiotropiumbromide. Yet another embodiment is a 2 mL pharmaceutical composition,such as a solution, containing about 15 μg tiotropium bromide. Yetanother embodiment is a 2 mL pharmaceutical composition, such as asolution, containing about 10 μg tiotropium bromide. Yet anotherembodiment is a 2 mL pharmaceutical composition, such as a solution,containing about 5 μg tiotropium bromide.

In another embodiment of the present invention, a therapeuticallyeffective amount of tiotropium may include from about 0.0001% to about0.030% by weight tiotropium bromide, including the followingintermediate ranges of tiotropium bromide: about 0.0002 wt % to about0.02 wt %; about 0.0003 wt % to about 0.01 wt %; about 0.0005 wt % toabout 0.008 wt %; about 0.0002 wt % to about 0.001 wt %; about 0.001 wt% to about 0.005 wt %; about 0.006 wt % to about 0.010 wt %; about 0.011wt % to about 0.015 wt %; about 0.016 wt % to about 0.020 wt %; about0.021 wt % to about 0.025 wt %; or about 0.026 wt % to about 0.030 wt %.

In additional embodiments, the complexing agent (such as disodium EDTA)is present in the pharmaceutical composition or solution at aconcentration of less than about 0.1% by weight, such as less than about0.09%, less than about 0.08%, less than about 0.07%, less than about0.06%, less than about 0.05%, less than about 0.04%, less than about0.03%, about 0.02%, or less than about 0.01% by weight.

In additional embodiments, the pharmaceutical composition or solutionmay contain about 0.01% complexing agent about 0.02% complexing agent,about 0.03% complexing agent, about 0.04% complexing agent, about 0.05%complexing agent, about 0.06% complexing agent, about 0.07% complexingagent, about 0.08% complexing agent about 0.09% complexing agent orabout 0.1% complexing agent by weight.

In additional embodiments, the pharmaceutical composition or solutionmay contains about 0.01% disodium EDTA, about 0.02% disodium EDTA, about0.03% disodium EDTA, about 0.04% disodium EDTA, about 0.05% disodiumEDTA, about 0.06% disodium EDTA, about 0.07% disodium EDTA about 0.08%disodium EDTA about 0.09% disodium EDTA or about 0.1% disodium EDTA byweight. In one preferred embodiment, the pharmaceutical composition orsolution contains about 0.01% disodium EDTA. In another preferredembodiment, the pharmaceutical composition or solution contains about0.02% disodium EDTA. In yet another preferred embodiment, thepharmaceutical composition or solution contains about 0.05% disodiumEDTA.

One embodiment is a pharmaceutical solution suitable for administrationwith a nebulizer consisting essentially of

-   -   (a) about 0.0005% to about 0.008% w/w tiotropium or a        pharmaceutically acceptable salt thereof,    -   (b) about 0% to about 0.008% disodium EDTA;    -   (c) about 0% to about 0.9% sodium chloride; and    -   (d) water,        based upon 100% total weight of the pharmaceutical solution,        wherein the pH of the pharmaceutical composition is about 2 to        about 4 (such as about 2.7). In one preferred embodiment, the        pharmaceutical solution is free, or substantially free, of        quaternary ammonium preservatives. In another preferred        embodiment, the pharmaceutical solution is free, or        substantially free, of preservatives.

In one embodiment, the pharmaceutical composition or solution providedherein has a long shelf life, i.e., it is stable during long termstorage. The pharmaceutical composition or solution may contain greaterthan about 80%, such as greater than about 85%, greater than about 90%,greater than about 95% or greater than about 98% of the initial amountof tiotropium or its salt in the pharmaceutical composition or solutionafter being stored for 3 or 6 months or 1, 2 or 3 years at 25° C. whenstored in a suitable LDPE container, cyclic olefin polymer container,cyclic olefin copolymer container, or glass container. The stability maybe determined using Arrhenius kinetics.

Another embodiment is a container containing a pharmaceuticalcomposition or solution of the present invention, wherein the volume ofthe composition or solution is from about 0.1 ml to about 5 ml, such asfrom about 1 ml to about 3 ml, or from about 1.5 ml to about 2.5 ml. Inanother embodiment, the volume of the tiotropium solution of the presentinvention is from about 0.05 ml to about 1.0 ml; such as from about 0.1ml to about 0.9 ml; from about 0.1 ml to about 0.8 ml; from about 0.1 mlto about 0.7 ml; from about 0.1 ml to about 0.6 ml; from about 0.1 ml toabout 0.5 ml; from about 0.1 ml to about 0.4 ml; from about 0.1 ml toabout 0.3 ml; or from about 0.1 ml to about 0.2 ml.

In another embodiment, the pharmaceutical composition of the presentinvention comprises about 0.002% to about 0.01% w/w tiotropium or anypharmaceutically acceptable salt thereof, about 0% to about 0.01% w/wEDTA, about 0.9% sodium chloride, wherein the composition is free ofpreservative and wherein the composition has a pH in the range of about2.0 to about 4.0.

Another embodiment is a prepackaged, sterile, premixed, premeasuredtiotropium inhalation solution for the relief of bronchospasm inpatients suffering from COPD.

Another embodiment of the present invention is to provide asubstantially benzalkonium chloride free tiotropium inhalation solutionto treat bronchospasm associated with COPD. In another embodiment, thepresent invention comprises one or more prefilled containers. Eachcontainer comprises a single unit dose of an aqueous solution comprisinga therapeutically effective amount of tiotropium for the treatment ofCOPD. In another embodiment, the present invention relates to a sterile,premixed, premeasured, substantially benzalkonium chloride freeinhalation solution comprising a single unit dose of a therapeuticallyeffective amount of tiotropium in a single container.

One embodiment is a prefilled container containing about 2 mL of anaqueous pharmaceutical composition consisting of (i) from about 10 toabout 80 μg of tiotropium bromide, (ii) sodium chloride, (iii)hydrochloric acid (e.g., in an amount sufficient to adjust the pH of thepharmaceutical composition, such as to about 2.5 to about 3.5), and (iv)about 0.01% by weight of disodium EDTA, wherein the composition is freeof preservative, and the composition has a pH of from about 2.5 to about3.5. The sodium chloride may be present at about 0.9% by weight. In oneembodiment, the pH of the pharmaceutical composition is about 2.7. Inanother embodiment, the pH of the pharmaceutical composition is about2.8. In yet another embodiment, the pH of the pharmaceutical compositionis about 2.9. In yet another embodiment, the pH of the pharmaceuticalcomposition is about 3.0.

Another embodiment is a prefilled container containing about 2 mL of anaqueous pharmaceutical composition consisting of (i) from about 10 toabout 80 μg of tiotropium bromide, (ii) sodium chloride, (iii)hydrochloric acid (e.g., in an amount sufficient to adjust the pH of thepharmaceutical composition, such as to about 2.5 to about 3.5), and (iv)about 0.02% by weight of disodium EDTA, wherein the composition is freeof preservative, and the composition has a pH of from about 2.5 to about3.5.

Yet another embodiment is a prefilled container containing about 2 mL ofan aqueous pharmaceutical composition consisting of (i) from about 10 toabout 80 μg of tiotropium bromide, (ii) sodium chloride, (iii)hydrochloric acid (e.g., in an amount sufficient to adjust the pH of thepharmaceutical composition, such as to about 2.5 to about 3.5), and (iv)about 0.05% by weight of disodium EDTA, wherein the composition is freeof preservative, and the composition has a pH of from about 2.5 to about3.5.

A further embodiment of the present invention is to provide a method fortreating or relieving bronchospasm associated with COPD comprisingadministering to a patient in need thereof a tiotropium inhalationformulation according to any of the embodiments described herein.

An additional embodiment of the present invention is to provide a kitand/or system for administering a bronchodilator to relieve bronchospasmassociated with COPD. In an alternative embodiment, the kit and/orsystem of the present invention comprises an inhalation solutioncomprising a therapeutically effective amount of tiotropium in aprepackaged, premeasured, premixed and/or single unit dose form for thetreatment of COPD. In another alternative embodiment, the prepackagedinhalation kit and/or system of the present invention provides one ormore premixed, premeasured single unit dose vials comprising atherapeutically effective amount of tiotropium for the treatment ofbronchospasm associated with COPD, and instructions for using the same.

More specifically, the present invention provides a kit for thetreatment, prevention or amelioration or one or more symptoms ofdiseases or disorders associated with broncho constriction whichcomprises:

(i) a nebulizer;

(ii) a nebulizable composition for the treatment, prevention oramelioration or one or more symptoms of diseases or disorders associatedwith bronchoconstriction which comprises:

(a) tiotropium or a salt thereof; and

(b) water.

Yet another embodiment is a kit comprising a nebulizer, instructions forusing the nebulizer and the unit dose vials containing thepharmaceutical compositions of the present invention.

In another embodiment of the present invention, the osmolality of theinhalation solution may be from about 200 to about 500 mOsm/kg. Inanother embodiment, the osmolality of the solution may be from about 275to about 325 mOsm/kg. In a further embodiment, the compositions of thepresent invention may comprise about 0.4 to about 1.0 weight percentionic salt.

Suitable tonicity adjusting agents may include, but are not limited to,ammonium carbonate, ammonium chloride, ammonium lactate, ammoniumnitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuthsodium tartrate, boric acid, calcium chloride, calcium disodium edetate,calcium gluconate, calcium lactate, citric acid, dextrose,diethanolamine, dimethyl sulfoxide, edetate disodium, edetate trisodiummonohydrate, fluorescein sodium, fructose, galactose, glycerin, lacticacid, lactose, magnesium chloride, magnesium sulfate, mannitol,polyethylene glycol, potassium acetate, potassium chlorate, potassiumchloride, potassium iodide, potassium nitrate, potassium phosphate,potassium sulfate, propylene glycol, silver nitrate, sodium acetate,sodium bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate,sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride,sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite,sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate,sodium succinate, sodium sulfate, sodium sulfite, sodium tartrate,sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine,urea, urethan, uridine, zinc sulfate, and mixtures thereof.

Suitable osmotic adjusting agents that may be used include, but are notlimited to, sodium chloride, potassium chloride, zinc chloride, calciumchloride and mixtures thereof. Other osmotic adjusting agents may alsoinclude, but are not limited to, mannitol, glycerol, dextrose andmixtures thereof.

Any cosolvent that is suitable for inhalation and capable of dissolvingor solubilizing the tiotropium in the mixture of cosolvent and water canbe used. Examples of suitable cosolvents include, for example, alcohols,ethers, hydrocarbons, and perfluorocarbons. Preferably, the cosolvent isa short chain polar alcohol. More preferably, the cosolvent is analiphatic alcohol having from one to six carbon atoms, such as ethanolor isopropanol. The most preferred cosolvent is ethanol. Examples ofsuitable hydrocarbons include n-butane, isobutane, pentane, neopentaneand isopentanes. Examples of suitable ethers include dimethyl ether anddiethyl ether. Examples of suitable perfluorocarbons includeperfluoropropane, perfluorobutane, perfluorocyclobutane, andperfluoropentane.

When ethanol is utilized as the cosolvent, the cosolvent is usuallypresent in an amount of from about 1% to about 40% by weight, based onthe total weight of the formulation. The ethanol should be present in anamount which fully dissolves or solubilizes tiotropium in the mixture ofethanol and water. Preferably, ethanol is present in amount sufficientto fully maintain the tiotropium in solution at freezing temperatures,such as 0° C. In general, as the temperature is decreased, thesolubility of active ingredient in ethanol is decreased. Therefore, anexcess of ethanol over the amount required to fully dissolve orsolubilize active ingredient at ambient or room temperature ispreferred. In this regard, ethanol is preferably present in an amount ofat least 10% by weight, more preferably at least 15% by weight, evenmore preferably at least 20% by weight, and most preferably at least 25%by weight. Based on the disclosure provided herein, one skilled in theart will recognize that lower concentrations of active ingredientusually require lower concentrations of cosolvent, and vice versa, inorder to form a stable solution.

Suitable surfactants that may be used include, but are not limited to,C5-20-fatty alcohols, C5-20-fatty acids, C5-20-fatty acid esters,lecithin, glycerides, propyleneglycol esters, polyoxyethylenes,polysorbates, sorbitan esters and/or carbohydrates. C5-20-fatty acids,propyleneglycol diesters and/or triglycerides and/or sorbitans of theC5-20-fatty acids are preferred, while oleic acid and sorbitan mono-,di- or trioleates are particularly preferred.

Suitable antioxidants that may be used include, but are not limited to,ascorbic acid, for example, provided that it has not already been usedto adjust the pH, vitamin A, vitamin E, tocopherols and similar vitaminsor pro-vitamins occurring in the human body.

The inhalation solution may be contained in a unit-dose, low-densitypolyethylene (LDPE) container, polypropylene container, or a cyclicpolyolefin container. Each unit-dose container may be disposed in a foilpouch, and each foil pouch may contain 2 or more unit-dose containers.Each foil pouch containing the unit dose container may be disposed in ashelf carton. The inhalation solution comprises a single unit dose of atherapeutically effective amount of tiotropium. Such system and/or kitmay provide such containers in prepackaged form. The container with aTWIST-FLEX′ top prefer, such top comprising an easy-to-grip tab-likehandle such that the container may be opened, for example, by twistingoff the tab by hand. The TWIST-FLEX′ top is advantageous in that itallows for easy dispensing of the solution, prevents spillage andeliminates the need to open the container or tearing by cutting ortearing off the top, or the like, thereby reducing cross-contamination.One or more of the semi-permeable single unit dose containers may beprepackaged in aluminum foil pouch, such that the foil provides aprotective barrier against environmental contaminants and light as ithelps to improves the shelf-life and stability of the inhalationsolution. Dispensing vials may include, but are not limited to, anycontainer comprising glass, low density polyethylene, polypropylene,cyclic polyolefins or any other material capable of preventing thesolution from leaking out of the container. The vial may be enclosed byany conventional means including, but not limited to, screw cap, heatseal, snap-on top, flip-top, twist-off stopper, peel away top, and thelike.

The inhalation solution of the present invention may be administered bynebulizer. Suitable nebulizers include, but are not limited to, a jetnebulizer, an ultrasonic nebulizer, vibrating mesh nebulizer and abreath actuated nebulizer. Preferably, the nebulizer is a jet nebulizerconnected to an air compressor with adequate airflow. The nebulizerbeing equipped with a mouthpiece or suitable face mask. The inhalationsolution may be administered by nebulizers manufactured, designed orsold by Omron, such as the Omron MICRO AIR™ Ultrasonic Nebulizer. Othernebulizers may also include those manufactured, designed, or sold byAerogen. Additionally, the formulations described herein can also benebulized using inhalers other than those described above, for examplejet-stream inhalers.

Yet another embodiment is a method of preparing a pharmaceuticalcomposition comprising about 0.0001% to about 0.03% by weight oftiotropium or a pharmaceutically acceptable salt thereof, water, about0.01% to about 0.1% by weight of a complexing agent, and about 0% toabout 0.9% by weight of sodium chloride, wherein the composition has apH ranging from about 2.5 to about 3.5 and is free of preservative. Theprocess includes the steps of:

-   -   (a) dissolving sodium chloride in water to form a solution;    -   (b) adding a complexing agent to the solution of step (a);    -   (c) adjusting the pH of the solution of step (b) (for example,        by adding hydrochloric acid) to about 2.5 to about 3.5;    -   (d) adding tiotropium or a pharmaceutically acceptable salt        thereof;    -   (e) filtering the solution of step (d); and    -   (f) filling a container with the solution of step (e).

The following non-limiting examples suitably illustrate thepharmaceutical compositions of the present invention.

Example 1

The pharmaceutical compositions of the invention may include thefollowing ingredients in amounts as provided in the following table:

Sr. No. Ingredients Range (% w/w) 1 Tiotropium Bromide 0.0005 to 0.1   2 Benzalkonium Chloride  0 to 0.008 3 Di Sodium EDTA 0.001 to 0.008   4Sodium Chloride 0 to 0.9 5 1N HCl 0 to 1.4 6 Water for injection q.s.

Example 2

The pharmaceutical compositions of the invention may include followingingredients and amounts:

Sr. No. Ingredients Range (% w/w) 1 Tiotropium Bromide 0.0005 to 0.1   2 Citric acid  0 to 0.008 3 Sodium citrate 0.001 to 0.008   4 SodiumChloride 0 to 0.9 5 1N HCl 0 to 1.4 6 Water for injection q.s.

The pharmaceutical compositions from Example 1 and Example 2 may besterilized by filtration (through a 0.2 micron filter) and filled into asuitable container. The solution compositions may be inserted into asuitable nebulizer and the patient breathes into the nebulizer todeliver the dosage into the lungs.

Example 3A

The pharmaceutical compositions of the invention may include thefollowing:

10 mcg/ 20 mcg/ 40 mcg/ 80 mcg/ Sr. 2 ml 2 ml 2 ml 2 ml No IngredientsQuantity (% w/w) 1 Tiotropium 0.0005 0.001 0.002 0.004 bromide anhydrouseq. to Tiotropium 2 Sodium chloride 0.9  3 Disodium edetate 0.001 4Hydrochloric acid q.s. to pH 2.7 as 1N HCl solution 5 Water forinjection q.s.

Manufacturing Process:

-   -   1. Collect 95% of batch quantity water for injection in        manufacturing vessel. Cool water for injection to 15-25° C.    -   2. Add and dissolve to it batch quantity of sodium chloride        under stirring. Check clarity of the solution.    -   3. Add and dissolve to it batch quantity of disodium edetate        under stirring. Check clarity of the solution.    -   4. Check pH and adjust pH to 2.7 using 1N HCl solution.    -   5. Add and dissolve to it batch quantity of tiotropium bromide        anhydrous under stirring. Check clarity of the solution.    -   6. Make up volume of bulk.    -   7. Filter bulk through 0.22μ PVDF filter.    -   8. Fill in suitable containers.

Example 3B

The pharmaceutical compositions in the table below may be prepared asdescribed in Example 3A.

10 mcg/ 20 mcg/ 40 mcg/ 80 mcg/ Sr. 2 ml 2 ml 2 ml 2 ml No IngredientsQuantity (% w/w) 1 Tiotropium 0.0005 0.001 0.002 0.004 bromide anhydrouseq. to Tiotropium 2 Sodium chloride 0.9  3 Disodium edetate 0.01 4Hydrochloric acid q.s. to pH 2.7 as 1N HCl solution 5 Water forinjection q.s.

The pharmaceutical compositions in the table above may also be preparedas with the pH adjusted to 2.8, 2.9, or 3.0.

Example 3C

The pharmaceutical compositions in the table below may be prepared asdescribed in Example 3A.

10 mcg/ 20 mcg/ 40 mcg/ 80 mcg/ Sr. 2 ml 2 ml 2 ml 2 ml No IngredientsQuantity (% w/w) 1 Tiotropium 0.0005 0.001 0.002 0.004 bromide anhydrouseq. to Tiotropium 2 Sodium chloride 0.9  3 Disodium edetate 0.02 4Hydrochloric acid q.s. to pH 2.7 as 1N HCl solution 5 Water forinjection q.s.

The pharmaceutical compositions in the table above may also be preparedas with the pH adjusted to 2.8, 2.9, or 3.0.

Example 3D

The pharmaceutical compositions in the table below may be prepared asdescribed in Example 3A.

10 mcg/ 20 mcg/ 40 mcg/ 80 mcg/ Sr. 2 ml 2 ml 2 ml 2 ml No IngredientsQuantity (% w/w) 1 Tiotropium 0.0005 0.001 0.002 0.004 bromide anhydrouseq. to Tiotropium 2 Sodium chloride 0.9  3 Disodium edetate 0.05 4Hydrochloric acid q.s. to pH 2.7 as 1N HCl solution 5 Water forinjection q.s.

The pharmaceutical compositions in the table above may also be preparedas with the pH adjusted to 2.8, 2.9, or 3.0.

Example 4

The below example illustrates the effect of different concentrations ofEDTA on the stability of the composition

4A 4B 4C mcg/ % mcg/ mcg/ # Ingredients 2 ml w/w 2 ml % w/w 2 ml % w/w 1Tiotropium 80 0.004 80 0.004 80 0.004 Bromide anhydrous eq. totiotropium 2 Disodium — — 20 0.001 200 0.01 EDTA 3 Sodium 18000 0.918000 0.9 18000 0.9 chloride 5 1N HCl q.s. to pH 2.7 solution 6 Waterfor qs qs qs qs qs qs injection pH of solution 2.69 2.71 2.7 Stabilitydata Related substances Impurity A (2-hydroxy-2,2-dithiophen-2-ylaceticacid) # 4A 4B 4C Initial 0.02 ND 0.01 1 M 2-8° C. 0.01 0.03 0.02 1 M_25°C./60% 0.05 0.06 0.05 RH 1 M_40° C./75% 0.17 0.16 0.2 RH Totalimpurities Initial 0.07 ND 0.06 1 M 2-8° C. 0.08 0.00 0.12 1 M_25°C./60% 0.13 0.09 0.16 RH 1 M_40° C./75% 0.26 0.17 0.39 RH Assay %Initial 101.5 101.1 103.1 1 M 2-8° C. 101.1 99.7 102.6 1 M_25° C./60%101.1 100.2 102.4 RH 1 M_40° C./75% 100.8 100.6 102.1 RH

Manufacturing Process:

-   -   1. 90% batch quantity of water for injection was collected in a        vessel.    -   2. Batch quantity of sodium chloride was added and dissolved        under stirring.    -   3. Batch quantity of disodium edetate was added and dissolved        under stirring.    -   4. pH was checked and adjusted to pH 2.7 using 1N HCL solution.    -   5. Batch quantity of Tiotropium Bromide was added and dissolved        under stirring.    -   6. Volume of bulk was made up.

Example 5

The below example illustrates the compositions with different pHadjusting agents such as citrate buffer and 1 N HCl

Sr. 5A 5B No. Ingredients mcg/2 ml % w/w mcg/2 ml % w/w 1 Tiotropium 800.004 80 0.004 Bromide anhydrous eq. to tiotropium 2 Disodium 20 0.00120 0.001 EDTA 3 Sodium 18000 0.9 18000 0.9 chloride 4 Citric acid 80000.40 — — monohydrate 5 Sodium 1200 0.06 — — citrate dihydrate 6 1N HCl —q.s. to pH 2.7 7 Water for qs qs qs qs injection pH of solution 2.652.71 Stability data Related substances (Impurity A (2-hydroxy-2,2-dithiophen-2-ylacetic acid) # 5A 5B Initial 0.02 ND 1 M 2-8° C. 0.030.03 1 M_25° C./60% RH 0.06 0.06 1 M_40° C./75% RH 0.18 0.16 Totalimpurities Initial 0.07 ND 1 M 2-8° C. 0.16 0 1 M_25° C./60% RH 0.260.09 1 M_40° C./75% RH 0.38 0.17 Assay % Initial 104.9 101.1 1 M 2-8° C.104.2 99.7 1 M_25° C./60% RH 104.4 100.2 1 M_40° C./75% RH 103.5 100.6

Manufacturing Process (5A)

-   -   1. 90% batch quantity of water for injection was collected in a        vessel.    -   2. Batch quantity of sodium chloride was added and dissolved        under stirring.    -   3. Batch quantity of disodium edetate was added and dissolved        under stirring.    -   4. Batch quantity of citric acid monohydrate was added and        dissolved under stirring.    -   5. Batch quantity of sodium citrate dihydrate was added and        dissolved under stirring.    -   6. Batch quantity of Tiotropium Bromide was added and dissolved        under stirring.    -   7. Volume of bulk was made up.

Manufacturing Process (5B)

-   -   1. 90% batch quantity of water for injection was collected in a        vessel.    -   2. Batch quantity of sodium chloride was added and dissolved        under stirring.    -   3. Batch quantity of disodium edetate was added and dissolved        under stirring.    -   4. pH was checked and adjusted to pH 2.7 using 1N HCL solution.    -   5. Batch quantity of Tiotropium Bromide was added and dissolved        under stirring.    -   6. Volume of bulk was made up.

Example 6

The below example illustrates the compositions at different pH ranges.

6A 6B 6C 6D Sr. mcg/ mcg/ mcg/ mcg/ No Ingredients 2 ml 2 ml 2 ml 2 ml %w/w 1 Tiotropium 80 80 80 80 0.004 Bromide anhydrous eq. to tiotropium 2Disodium EDTA 20 20 20 20 0.001 3 Sodium chloride 18000 18000 1800018000 0.9 5 1N HCl q.s. to q.s. to q.s. to q.s. to — pH 2.7 pH 2.9 pH2.4 pH 2.2 6 Water for injection qs qs qs qs qs Stability data Relatedsubstances Impurity A (2-hydroxy-2,2-dithiophen-2-ylacetic acid) # 6A 6B6C 6D Initial 0.03 0.03 0.02 0.03 1 M 2-8° C. 0.04 0.05 0.05 0.06 1M_25° C./60% RH 0.07 0.09 0.09 0.12 1 M_40° C./75% RH 0.21 0.27 0.190.23 Total impurities Initial 0.19 0.19 0.19 0.18 1 M 2-8° C. 0.18 0.200.21 0.18 1 M_25° C./60% RH 0.20 0.13 0.23 0.26 1 M_40° C./75% RH 0.330.41 0.33 0.35 Assay % Initial 97.9 102.5 103.1 102.8 1 M 2-8° C. 95.6102.30 102.2 102.2 1 M_25° C./60% RH 95.6 102.3 101.6 101.9 1 M_40°C./75% RH 95.0 101.4 100.8 101.2

Manufacturing Process:

-   -   1. 90% batch quantity of water for injection was collected in a        vessel    -   2. Batch quantity of sodium chloride was added and dissolved        under stirring.    -   3. Batch quantity of disodium edetate was added and dissolved        under stirring.    -   4. pH was checked and adjusted as desired using 1N HCL solution    -   5. Batch quantity of Tiotropium Bromide was added and dissolved        under stirring.    -   5. Volume of bulk was made up.

Example 7

The below example illustrates compositions with different fill volumesper unit dosage form

7A 7B 7C Sr. 80 mcg/ 80 mcg/ 80 mcg/ No. Ingredients 1 ml % w/w 2 ml %w/w 3 ml % w/w 1 Tiotropium 80 0.008 80 0.004 80 0.0026 Bromideanhydrous eq. to tiotropium 2 Disodium 20 0.002 20 0.001 20 0.0006 EDTA3 Sodium 9000 0.9 18000 0.9 27000 0.9 chloride 4 1N HCl q.s. to pH 2.7 5Water for q.s 1 ml q.s 2 ml q.s 3 ml injection pH of solution 2.69 2.712.68 Related substances Impurity A (2-hydroxy-2,2-dithiophen-2-ylaceticacid) # 7A 7B 7C Initial ND ND ND 1 M 2-8° C. 0.01 ND ND 1 M_25° C./60%RH 0.04 0.09 0.04 1 M_40° C./75% RH 0.15 0.17 0.15 Total impuritiesInitial 0.09 0 0 1 M 2-8° C. 0.11 0.16 0 1 M_25° C./60% RH 0.17 0.190.04 1 M_40° C./75% RH 0.29 0.28 0.15 Assay % Initial 103.2 102.9 104.11 M 2-8° C. 102.9 102.7 103.4 1 M_25° C./60% RH 101.8 101.8 102.1 1M_40° C./75% RH 100.9 102.1 101.4

Manufacturing Process:

-   -   1. 90% batch quantity of water for injection was collected in a        vessel.    -   2. Batch quantity of sodium chloride was added and dissolved        under stirring.    -   3. Batch quantity of disodium edetate was added and dissolved        under stirring.    -   4. pH was checked and adjusted to pH 2.7 using 1N HCL solution.    -   5. Batch quantity of Tiotropium Bromide was added and dissolved        under stirring.    -   6. Volume of bulk was made up.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and application of the presentinvention. It is therefore to be understood that numerous modificationsmay be made to the illustrative embodiments and that other arrangementsmay be devised without departing from the spirit and scope of thepresent invention as described.

1-30. (canceled)
 31. A stable inhalation solution for the treatment of arespiratory disease, the inhalation solution being suitable foradministration with a nebulizer, the inhalation solution comprising: (i)tiotropium bromide; (ii) citric acid; (iii) sodium citrate; (iv) sodiumchloride; and (ii) water, wherein the inhalation solution issubstantially free of preservative and complexing agent and has anosmolality of about 275 to about 325 mOsm/kg, and the inhalationsolution is contained in a prefilled container.
 32. The inhalationsolution according to claim 31, wherein the tiotropium bromide isanhydrous tiotropium bromide.
 33. The inhalation solution according toclaim 31, wherein the tiotropium bromide is anhydrous amorphoustiotropium bromide.
 34. The inhalation solution according to claim 31,wherein the tiotropium bromide is tiotropium bromide monohydrate. 35.The inhalation solution according to claim 31, wherein the solutioncomprises about 10 to about 80 micrograms of tiotropium bromide.
 36. Theinhalation solution according to claim 31, wherein the volume of theinhalation solution is between about 0.1 ml to about 5 ml.
 37. Theinhalation solution according to claim 31, wherein the volume of theinhalation solution is about 2 ml.
 38. The inhalation solution accordingto claim 31, wherein the pH of the inhalation solution is about 2.5 toabout 3.0.
 39. The inhalation solution according to claim 31, whereinthe pH of the inhalation solution is about 3.0.
 40. The inhalationsolution according to claim 31, wherein the pH of the inhalationsolution is about 2.9.
 41. The inhalation solution according to claim31, wherein the pH of the inhalation solution is about 2.8.
 42. Theinhalation solution according to claim 31, wherein the pH of theinhalation solution is about 2.7.
 43. The inhalation solution accordingto claim 31, wherein the container is a low density polyethylenecontainer.
 44. The inhalation solution according to claim 31, whereinthe inhalation solution contains greater than 90% of the initial amountof tiotropium bromide after being stored for 2 years at 25° C.
 45. Theinhalation solution according to claim 31, wherein the inhalationsolution contains greater than 95% of the initial amount of tiotropiumbromide after being stored for 2 years at 25° C.
 46. The inhalationsolution according to claim 31, wherein the inhalation solution containsgreater than 98% of the initial amount of tiotropium bromide after beingstored for 2 years at 25° C.
 47. The inhalation solution according toclaim 31, wherein the solution comprises 0.9% by weight of sodiumchloride.
 48. A stable inhalation solution for the treatment of arespiratory disease, the inhalation solution being suitable foradministration with a nebulizer, the inhalation solution comprising: (i)tiotropium bromide; (ii) a buffer; (iii) water; and (iv) a complexingagent in an amount of less than 0.1% by weight, wherein the inhalationsolution is substantially free of preservative.
 49. The inhalationsolution according to claim 48, wherein the tiotropium bromide isanhydrous tiotropium bromide.
 50. The inhalation solution according toclaim 48, wherein the tiotropium bromide is anhydrous amorphoustiotropium bromide.
 51. The inhalation solution according to claim 48,wherein the tiotropium bromide is tiotropium bromide monohydrate. 52.The inhalation solution according to claim 48, wherein the solutioncomprises about 10 to about 80 micrograms of tiotropium bromide.
 53. Theinhalation solution according to claim 48, wherein the volume of theinhalation solution is between about 0.1 ml to about 5 ml.
 54. Theinhalation solution according to claim 48, wherein the volume of theinhalation solution is about 2 ml.
 55. The inhalation solution accordingto claim 48, wherein the pH of the inhalation solution is about 2.5 toabout 3.0.
 56. The inhalation solution according to claim 48, whereinthe pH of the inhalation solution is about 3.0.
 57. The inhalationsolution according to claim 48, wherein the pH of the inhalationsolution is about 2.9.
 58. The inhalation solution according to claim48, wherein the pH of the inhalation solution is about 2.8.
 59. Theinhalation solution according to claim 48, wherein the pH of theinhalation solution is about 2.7.
 60. The inhalation solution accordingto claim 48, wherein the inhalation solution contains greater than 90%of the initial amount of tiotropium bromide after being stored for 2years at 25° C.
 61. The inhalation solution according to claim 48,wherein the inhalation solution contains greater than 95% of the initialamount of tiotropium bromide after being stored for 2 years at 25° C.62. The inhalation solution according to claim 48, wherein theinhalation solution contains greater than 98% of the initial amount oftiotropium bromide after being stored for 2 years at 25° C.
 63. Theinhalation solution according to claim 48, wherein the solution furthercomprises 0.9% by weight of sodium chloride.
 64. The inhalation solutionaccording to claim 48, wherein the inhalation solution has an osmolalityof about 275 to about 325 mOsm/kg.
 65. A stable inhalation solution foradministration with a nebulizer, the inhalation solution comprising: (i)tiotropium bromide; (ii) a buffer; and (iii) water, wherein theinhalation solution is substantially free of preservative and complexingagent.
 66. The inhalation solution according to claim 65, wherein thetiotropium bromide is anhydrous tiotropium bromide.
 67. The inhalationsolution according to claim 65, wherein the tiotropium bromide isanhydrous amorphous tiotropium bromide.
 68. The inhalation solutionaccording to claim 65, wherein the tiotropium bromide is tiotropiumbromide monohydrate.
 69. The inhalation solution according to claim 65,wherein the solution comprises about 10 to about 80 micrograms oftiotropium bromide.
 70. The inhalation solution according to claim 65,wherein the volume of the inhalation solution is between about 0.1 ml toabout 5 ml.
 71. The inhalation solution according to claim 65, whereinthe volume of the inhalation solution is about 2 ml.
 72. The inhalationsolution according to claim 65, wherein the pH of the inhalationsolution is about 2.5 to about 3.0.
 73. The inhalation solutionaccording to claim 65, wherein the pH of the inhalation solution isabout 3.0.
 74. The inhalation solution according to claim 65, whereinthe pH of the inhalation solution is about 2.9.
 75. The inhalationsolution according to claim 65, wherein the pH of the inhalationsolution is about 2.8.
 76. The inhalation solution according to claim65, wherein the pH of the inhalation solution is about 2.7.
 77. Theinhalation solution according to claim 65, wherein the inhalationsolution contains greater than 90% of the initial amount of tiotropiumbromide after being stored for 2 years at 25° C.
 78. The inhalationsolution according to claim 65, wherein the inhalation solution containsgreater than 95% of the initial amount of tiotropium bromide after beingstored for 2 years at 25° C.
 79. The inhalation solution according toclaim 65, wherein the inhalation solution contains greater than 98% ofthe initial amount of tiotropium bromide after being stored for 2 yearsat 25° C.
 80. The inhalation solution according to claim 65, wherein thesolution further comprises 0.9% by weight of sodium chloride.
 81. Theinhalation solution according to claim 65, wherein the inhalationsolution has an osmolality of about 275 to about 325 mOsm/kg.
 82. Astable inhalation solution for the treatment of a respiratory disease,the inhalation solution being suitable for administration with anebulizer, the inhalation solution comprising: (i) tiotropium bromide;(ii) a buffer; (iii) sodium chloride; and (iv) water, wherein theinhalation solution is substantially free of preservative and complexingagent and has an osmolality of about 275 to about 325 mOsm/kg, and theinhalation solution is contained in a prefilled container.
 83. Theinhalation solution according to claim 82, wherein the tiotropiumbromide is anhydrous tiotropium bromide.
 84. The inhalation solutionaccording to claim 82, wherein the tiotropium bromide is anhydrousamorphous tiotropium bromide.
 85. The inhalation solution according toclaim 82, wherein the tiotropium bromide is tiotropium bromidemonohydrate.
 86. The inhalation solution according to claim 82, whereinthe solution comprises about 10 to about 80 micrograms of tiotropiumbromide.
 87. The inhalation solution according to claim 82, wherein thevolume of the inhalation solution is between about 0.1 ml to about 5 ml.88. The inhalation solution according to claim 82, wherein the volume ofthe inhalation solution is about 2 ml.
 89. The inhalation solutionaccording to claim 82, wherein the pH of the inhalation solution isabout 2.5 to about 3.0.
 90. The inhalation solution according to claim82, wherein the pH of the inhalation solution is about 3.0.
 91. Theinhalation solution according to claim 82, wherein the pH of theinhalation solution is about 2.9.
 92. The inhalation solution accordingto claim 82, wherein the pH of the inhalation solution is about 2.8. 93.The inhalation solution according to claim 82, wherein the pH of theinhalation solution is about 2.7.
 94. The inhalation solution accordingto claim 82, wherein the inhalation solution contains greater than 90%of the initial amount of tiotropium bromide after being stored for 2years at 25° C.
 95. The inhalation solution according to claim 82,wherein the inhalation solution contains greater than 95% of the initialamount of tiotropium bromide after being stored for 2 years at 25° C.96. The inhalation solution according to claim 82, wherein theinhalation solution contains greater than 98% of the initial amount oftiotropium bromide after being stored for 2 years at 25° C.
 97. Theinhalation solution according to claim 82, wherein the solutioncomprises 0.9% by weight of sodium chloride.